Synthesis of N-substituted 4-(4-hydroxyphenyl)piperidines, 4-(4- hydroxybenzyl)piperidines, and (±)-3-(4-hydroxyphenyl)pyrrolidines: Selective antagonists at the 1A/2B NMDA receptor subtype

Article abstract of DOI:10.1021/jm990428c

Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typically small molecules that consist of a 4-benzyl- or a 4-phenylpiperidine with an ω-phenylalkyl substituent on the heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a 4-hydroxy substituent on the ω-phenyl group. In this study, the position of this 4- hydroxy substituent was transferred from the ω-phenyl group to the benzyl or phenyl group located on the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes show that high-potency antagonists at the NR1A/2B subtype are obtained employing N-(ω-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4- hydroxybenzyl)piperidine, and (±)3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC₅₀ = 0.022 μM), 33 (IC₅₀ = 0.059 μM), and 40 (IC₅₀ = 0.017 μM), respectively. These high-potency antagonists are > 1000 times more potent at the NR1A/2B subtype than at either the NR1A/2A or NR1A/2C subtypes. The binding affinities of 21 at α₁-adrenergic receptors ([³H]prazosin, IC₅₀ = 0.54 μM) and dopamine D2 receptors ([³H]raclopride, IC₅₀ = 1.2 μM) are reduced by incorporating a hydroxy group onto the 4-position of the piperidine ring and the β-carbon of the N- alkyl spacer to give (±)-27: IC₅₀ NR1A/2B, 0.026; α₁, 14; D2, 105 μM. The high-potency phenolic antagonist 21 and its low-potency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal electroshock- induced seizure (MES) study (ED₅₀ (iv) = 0.23 and 0.56 mg/kg, respectively). These data indicate that such compounds penetrate the blood- brain barrier but their MES activity may not be related to NMDA receptor antagonism.

Full text of DOI:10.1021/jm990428c

984
J . Med. Chem. 2000, 43, 984-994
Syn th esis of N-Su bstitu ted 4-(4-Hyd r oxyp h en yl)p ip er id in es,
4-(4-Hyd r oxyben zyl)p ip er id in es, a n d (()-3-(4-Hyd r oxyp h en yl)p yr r olid in es:
Selective An ta gon ists a t th e 1A/2B NMDA Recep tor Su btyp e
Anthony P. Guzikowski,†,‡ Amir P. Tamiz,§ Manuel Acosta-Burruel,† Soo Hong-Bae,† Sui Xiong Cai,†,|
J on E. Hawkinson,†, J ohn F. W. Keana,*,§ Suzanne R. Kesten,∇ Christina T. Shipp,§ Minhtam Tran,†
Edward R. Whittemore,† Richard M. Woodward,*,† J on L. Wright,∇ and Zhang-Lin Zhou†
CoCensys, Inc., 213 Technology Drive, Irvine, California 92618, Department of Chemistry, University of Oregon,
Eugene, Oregon 97403, and Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company,
2800 Plymouth Road, Ann Arbor, Michigan 48105
Received August 23, 1999
Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typically small molecules
that consist of a 4-benzyl- or a 4-phenylpiperidine with an ω-phenylalkyl substituent on the
heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a
4-hydroxy substituent on the ω-phenyl group. In this study, the position of this 4-hydroxy
substituent was transferred from the ω-phenyl group to the benzyl or phenyl group located on
the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine
were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes
show that high-potency antagonists at the NR1A/2B subtype are obtained employing N-(ω-
phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4-hydroxybenzyl)piperidine, and (()-
3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC50 ) 0.022 µM), 33 (IC50 ) 0.059 µM),
and 40 (IC50 ) 0.017 µM), respectively. These high-potency antagonists are >1000 times more
potent at the NR1A/2B subtype than at either the NR1A/2A or NR1A/2C subtypes. The binding
affinities of 21 at R1-adrenergic receptors ([3H]prazosin, IC50 ) 0.54 µM) and dopamine D2
receptors ([3H]raclopride, IC50 ) 1.2 µM) are reduced by incorporating a hydroxy group onto
the 4-position of the piperidine ring and the â-carbon of the N-alkyl spacer to give (()-27: IC50
NR1A/2B, 0.026; R1, 14; D2, 105 µM. The high-potency phenolic antagonist 21 and its low-
potency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal
electroshock-induced seizure (MES) study (ED50 (iv) ) 0.23 and 0.56 mg/kg, respectively). These
data indicate that such compounds penetrate the blood-brain barrier but their MES activity
may not be related to NMDA receptor antagonism.
In tr od u ction
uted throughout the brain, whereas the NR2 subunits
exhibit distinct regional distribution patterns.4 Hence,
the activity of subtype-selective NR2 antagonists should
be limited to specific regions in the brain. Regional
specificity may improve the side effect profile associated
with broad-spectrum NMDA receptor antagonists.
N-Methyl-D-aspartate (NMDA) receptor antagonists
are being investigated as potential therapeutic agents
for diseases associated with acute and chronic neuronal
excitotoxicity such as focal ischemia, epilepsy, and
Parkinson’s disease.1 However, undesired side effects
such as neurotoxicity, sedation, and psychotomimetic
behaviors have limited the usefulness of these antago-
nists in the clinic.2 Subtype-selective NMDA receptor
antagonists may offer one means to limit these side
effects.3 Native NMDA receptors are heterooligomeric
assemblies of two classes of subunits. These subunits
are NMDA receptor 1 (NR1) of which eight isoforms are
known and NMDA receptor 2 (NR2) that consists of four
distinct types (A-D), each of which is transcribed from
a separate gene. The NR1 subunits are widely distrib-
Many NR2B-selective antagonists reported in the
literature (e.g. 1,5 2,6 3,7 and 48) are 4-benzyl- or
4-phenylpiperidines with an ω-(4-hydroxyphenyl)alkyl
or ω-(4-hydroxyphenoxy)alkyl substituent on the het-
erocyclic nitrogen atom. Recently, we reported that the
piperidine ring is not requisite for potent NR2B antago-
nism since open chain alkylamines, such as bis(phenyl-
alkyl)amine 5, are also potent antagonists.9 Interest-
ingly, even cinnamides 6 and 7 are moderate NR2B
antagonists.10 These amides are of special interest since
antagonist potency is retained even though the p-
hydroxy group, which is critical for potency in this
series,11 is located on opposite ends of the two molecules.
* To whom correspondence should be addressed. Tel: 541-346-4609.
Fax: 541-346-0487. E-mail: jkeana@oregon.uoregon.edu.
† CoCensys, Inc.
§ University of Oregon.
Our objective herein is to determine whether the
transposition of the hydroxy group with retention of
potency that is observed for 6 and 7 can be extended to
a piperidine or pyrrolidine series of antagonists. There-
fore, selected N-substituted 4-(4-hydroxyphenyl)pip-
eridines, 4-(4-hydroxybenzyl)piperidines, and (()-3-(4-
3 Parke-Davis Pharmaceutical Research.
‡ Current address: Marker Gene Technologies, Inc., 1850 Millrace
Dr., Eugene, OR 97403.
| Current address: Cytovia, Inc., 6650 Nancy Ridge Dr., San Diego,
CA 92121.
Current address: Elan Pharmaceuticals, 3760 Haven Ave., Menlo
Park, CA 94025.
10.1021/jm990428c CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/15/2000

Selective Antagonists at 1A/ 2B NMDA Receptor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 985
Sch em e 1a
a
(a) n-BuLi, THF, -78 °C; (b) 1-benzyl-4-piperidone, THF, -78
°C; (c) concd HCl in EtOH (1:1), reflux; (d) NH4OH, MeOH/H2O;
(e) H2, Pd/C (10%), EtOH, 25 °C; (f) n-BuLi, THF, -78 °C; (g)
4-cyanopyridine, THF, -78 to 0 °C; (h) aq HCl, 25 °C; (i) N2H4,
KOH, ethylene glycol, 140 °C; (j) H2, PtO2, MeOH, aq HCl, 25 °C;
(k) HBr (48% in H2O), reflux.
anisole, gave methoxyphenylpiperidines 17 and 18.
Demethylation of 17 with BBr3 in CH2Cl2 gave 19.
Subsequently, it was found more convenient to directly
N-alkylate phenolic piperidine 10 employing an alkyl-
ating agent with NaHCO3 in DMF. This procedure did
not result in any observable O-alkylation and was used
to prepare 20-23. In a similar manner, alkylation of
11 gave 4-hydroxypiperidine 24. Treatment of 24 with
aqueous HCl in refluxing EtOH gave tetrahydropyridine
25. Racemic alcohols 26 and 27 were prepared by
reaction of 4-phenylbutane 1,2-epoxide16 with piperidine
10 or 11 in DMF. Compound 29 was prepared by
demethylation of 2817 (BBr3, CH2Cl2) followed by reac-
tion of the corresponding phenol (not shown) with
4-phenylpiperidine. Where appropriate, amine free bases
were converted to salts by treatment with an acid in
MeOH.
N-Substituted 4-(4-hydroxybenzyl)piperidines were
synthesized as shown in Scheme 3. Phenol 30 was
prepared by N-alkylation of methoxybenzylpiperidine
14 followed by demethylation. Acetylenes 31 and 32
were synthesized by N-alkylation of 15 with either
3-tosyloxy-1-propyne or 4-tosyloxy-1-butyne,18 respec-
tively, followed by a Pd-catalyzed coupling of the result-
ing terminal alkynes (not shown) with iodobenzene.
Hydrogenation of 31 gave 33.
hydroxyphenyl)pyrrolidines were prepared and assayed
for NMDA receptor antagonism employing the NR1A/
2A, NR1A/2B, and NR1A/2C subtypes. Additionally,
selected molecules were evaluated for R1-adrenergic
([3H]prazosin) and dopamine D2 ([3H]raclopride) binding
activity and for in vivo anticonvulsant activity.
Ch em istr y
Syn th esis. The preparation of 4-(4-hydroxyphenyl)-
piperidine12 (10) was performed according to general
literature procedures13 starting from 4-benzyloxybro-
mobenzene (8; Scheme 1). Treatment of 8 with n-BuLi
followed by addition of 1-benzyl-4-piperidone gave al-
cohol 9.14 Heating 9 in a solution of aqueous ethanolic
HCl resulted in elimination of the hydroxy group and
removal of the O-benzyl protecting group (structure not
shown). Conversion of this intermediate to the free base
(NH4OH, MeOH/H2O) followed by reduction and con-
comitant N-debenzylation (H2, Pd/C) gave 10. The
4-hydroxypiperidine analogue 1114 was prepared by
selective hydrogenolysis of 9. Treatment of 14, which
was prepared from 12 by methods described in the
patent literature,15 with refluxing aqueous HBr gave the
corresponding phenol 15.
The synthesis of (()-3-(4-hydroxyphenyl)pyrrolidines
is shown in Scheme 4. Maleic acid diethyl ester 35 was
prepared via the general method of Dean and Blum19
by the initial treatment of 4-methoxybenzylcyanide (34)
with glyoxylic acid followed by ethanolysis of the result-
ing nitrile (not shown). Hydrogenation of 35 to the
The synthesis of N-substituted 4-phenylpiperidines is
shown in Scheme 2. N-Alkylation of 16,13 which was
prepared as described for 10 but starting from 4-bromo-

986 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Guzikowski et al.
Sch em e 2a
Sch em e 3a
a
(a) 1-Phenyl-4-tosyloxybutane, K2CO3, MeCN, reflux; (b) BBr3,
CH2Cl2, 0-25 °C; (c) 3-tosyloxy-1-propyne or 4-tosyloxy-1-butyne,
DMF, NaHCO3, 80 °C; (d) iodobenzene, Pd(PPh3)4, pyrrolidine, 25
°C; (e) H2, Pd/C (20%), THF:MeOH (1:1), 25 °C.
Sch em e 4a
a
(a) Glyoxylic acid, K2CO3, MeOH, reflux; (b) H2SO4, EtOH,
reflux; (c) H2, Pd/C (10%), EtOH, 25 °C; (d) LiAlH4, THF, reflux;
(e) methanesulfonyl chloride, TEA, DMAP, CH2Cl2, 25 °C; (f)
4-phenylbutylamine (neat) or 5-phenylpentylamine (neat), 100 °C;
(g) BBr3, CH2Cl2, 25 °C.
37 and 38, respectively. Demethylation of 37 and 38
gave the corresponding phenols 39 and 40.
Electr op h ysiology in Xen opu s Oocytes. Potency
and subunit selectivity (see Table 1) were determined
by electrical recordings under steady-state conditions
in Xenopus oocytes expressing three binary combina-
tions of cloned rat NMDA receptor subunits (NR1A
expressed in combination with either NR2A, NR2B, or
NR2C). The IC50 values were derived by curve fitting
the concentration-inhibition data pooled from 1-7
separate experiments (see ref 9a for details).
Ra d ioliga n d Bin d in g Stu d ies. Selected compounds
were assayed for R1-adrenergic and dopamine D2 activ-
ity employing [3H]prazosin21 and [3H]raclopride22 bind-
ing assays, respectively (see Table 2). Test compounds
were evaluated at nine concentrations in duplicate (see
Experimental Section for details). IC50 values were
determined by fitting the data to the sigmoidal equation
in Prism.
a
(a) 1-Bromobutane or 1-phenyl-4-tosyloxybutane, K2CO3, MeCN,
reflux; (b) HBr or HCl or citric acid, MeOH, 25 °C; (c) BBr3, CH2Cl2,
0-25 °C; (d) 1-bromo-3-phenylpropane or 1-phenyl-4-tosyloxy-
butane or 2-benzyloxyethyl mesylate or 1-phenyl-5-tosyloxypen-
tane, NaHCO3, DMF, 80 °C; (e) concd HCl in EtOH (1:1), reflux;
(f) 4-phenylbutane 1,2-epoxide, DMF, 80 °C; (g) 4-phenylpiperidine,
NaHCO3, MeCN, reflux.
succinate, followed by ester reduction (LiAlH4) and
mesylation of the resulting diol, yielded dimesylate 36.
The reaction of 36 with neat 4-phenylbutylamine or
5-phenylpentylamine20 gave methoxyphenylpyrrolidines

Selective Antagonists at 1A/ 2B NMDA Receptor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 987
Ta ble 1. Functional Antagonism of N-Substituted 4-Phenylpiperidines, 4-Benzylpiperidines, and (()-3-Phenylpyrrolidines at NMDA
Receptor Subtypes

988 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Ta ble 1 (Continued)
Guzikowski et al.
a
IC50 values ((SEM) were determined by electrical recordings in Xenopus oocytes expressing the various NMDA receptor combinations.
For all compounds n g 3 at NR1A/2B. With the exception of 29, n g 2 at other subunit combinations. For 29, n ) 1 at NR1A/2A. b The data
for 41 are presented with 95% confidence limits; see ref 25.
Ta ble 2. R1-Adrenergic and Dopamine D2 Receptor Potencies
and Mouse MES Activity for N-Substituted 4-Phenylpiperidines
and 4-Hydroxy-4-phenylpiperidines
iv administration. ED50 values (95% confidence limits)
are given in Table 2 (see Experimental Section for
details).
IC50 (µM)
ED50 (mg/kg)
mouse MESc
Resu lts a n d Discu ssion
a
compd no.
R1
D2b
0.41
1.2
22
5.9
105
An ta gon ist P oten cy a t NMDA Recep tor Su b-
typ es. The goal of this study was to determine if high-
potency antagonists for the NR1A/2B subtype could be
obtained by tethering a 4-hydroxyphenyl or 4-hydroxy-
benzyl substituent onto the 4-position of an N-(ω-
phenylalkyl)piperidine or the 3-position of an N-(ω-
phenylalkyl)pyrrolidine. As a starting point, we chose
to prepare derivatives of 4-phenyl-1-(4-phenylbutyl)-
piperidine (PPBP, 41), a potent σ receptor ligand.24a
Compound 41 is an unsubstituted analogue of the NR2B
and D2 antagonist haloperidol25a and decreases brain
injury after focal ischemia in cats.24b Like haloperidol,
compound 41 is a moderately potent NR1A/2B antago-
18
21
24
26
27
1.7d
0.54
2.2
0.56 (0.33-0.94)
0.23 (0.10-0.51)
2.3 (1.3-4.1)
0.46 (0.25-0.84)
5.7 (3.8-8.7)
1.4
14
a
Inhibition of [3H]prazosin binding in rat brain cortical mem-
branes. Inhibition of [3H]raclopride binding in rat brain striatal
b
membranes. c ED50 values and 95% confidence limits for protection
against MES seizures in mice. A minimum of 24 animals were
employed for each test compound.
In Vivo Mea su r em en ts. Anticonvulsant effects for
five compounds were measured using a mouse MES
model.23 Seizure protection was measured 2 min after

Selective Antagonists at 1A/ 2B NMDA Receptor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 989
nist (IC50 ) 2.2 µM, Table 1).25b Each phenyl group of
41 was separately substituted at the para position with
a hydroxy group to give either 21 or 29. Compound 21
(IC50 ) 0.022 µM) is 100 times more potent at NR1A/2B
than 41, while compound 29 (IC50 ) 0.23 µM) is 10-fold
more potent than 41. The increased potency of both 21
and 29 relative to 41 suggests that such 4-phenylpip-
eridines may orientate in opposite directions within the
receptor pocket in order to take advantage of a putative
hydrogen bond interaction. Alternatively, these data
may also indicate that the receptor pocket possesses two
independent phenolic binding domains, one of which
may accommodate 21 and the other 29. This latter
possibility seems unlikely in the case of the N-(phenyl-
alkyl)cinnamide series of NR1A/2B antagonists,10b which
exhibits a SAR similar to those of the piperidine- and
bis(phenylalkyl)amine-based antagonists.9b The dihy-
droxycinnamide resulting from replacement of the Cl
of 7 by OH is about 170-fold less potent than 7,10b
indicating that a second OH group is detrimental to
potency.
measured from the para carbon of one phenyl ring to
the hydroxyl oxygen of the other ring) of several NR1A/
2B antagonists in a fully extended, energy-minimized
conformation.9b For piperidine-based antagonists, the
length ranged from 13.9 Å for 1 (NR1A/2B IC50 ) 0.11
µM) to 15 Å for 2 (NR1A/2B IC50 ) 0.009 µM). The
calculated lengths for 4-phenylpiperidine 21, 4-benzyl-
piperidine 33, and 4-phenylpyrrolidine 40 (15.6, 14.0,
and 15.8 Å, respectively) are similar. By way of com-
parison, the length of the most potent of the N-
(phenylalkyl)cinnamides tested, namely, N-(4-phenyl-
butyl)-4-hydroxycinnamide (NR1A/2B IC50 ) 0.077 µM),
is 17.5 Å.10b
The new NR1A/2B antagonists herein described gen-
erally show little or no antagonist potency at the NR1A/
2A and NR1A/2C subtypes. With the exception of 20,
all compounds having potency less than 0.1 µM at NR1A/
2B are at least 1000-fold more selective versus either
NR1A/2A or NR1A/2C. For 20, the selectivity for NR1A/
2B is approximately 700 times that for NR1A/2A.
In ter a ction a t Oth er Recep tor Typ es. Selected
molecules were screened for activity at R1-adrenergic
and dopamine D2 receptors using radioligand binding
assays (see Table 2). Activity at these sites was viewed
as a liability for a clinically useful drug. Compound 21
shows moderate affinity for these receptors. The affini-
ties may be decreased by placing a hydroxy group on
the 4-position of the piperidine ring (24) or on the
â-carbon of the N-alkyl spacer (26). Further reduction
is obtained by placing hydroxy groups at both positions
(27). The lessened affinities at R1 and D2 receptors come
without loss of potency at NR1A/2B. Similar observa-
tions have been made for certain other NR1A/2B an-
tagonists.7
Compound 21 was assayed by Novascreen.26 In a
nonselective σ receptor assay, compound 21 exhibited
98.5% inhibition of [3H]DTG binding at 1 µM. The
activity of 21 at σ receptors is not surprising since it is
a structural analogue of 41, a known σ ligand.24a
In Vivo Activity. Selected molecules were assayed
for in vivo anticonvulsant activity employing a mouse
MES model. The highly potent NR1A/2B antagonist 21
and the low-potency antagonist 18 are both potent
anticonvulsants (see Table 2) when administered iv
indicating their ability to penetrate the blood-brain
barrier. The lack of correlation between NR1A/2B po-
tency and MES activity for these two compounds leaves
the mechanism for this activity in question.
Hydroxylation of 21 either at the 4-position of the
piperidine ring (i.e., 24) or at the â-position of the alkyl
spacer (i.e., 26) reduces MES activity 10- and 2-fold,
respectively. Hydroxylation of both positions (27) re-
duces MES activity approximately 25-fold. The reduc-
tion of MES activity may result from a reduced ability
of these antagonists to penetrate the blood-brain bar-
rier and/or reduced activity at the site(s) responsible for
anticonvulsant activity.
Removing the phenyl group from the butyl chain of
21 (i.e., 19) reduces the potency approximately 3000-
fold. The reduction in potency is likely the result of a
reduced hydrophobic interaction that is important for
docking the ligand to the receptor pocket. Decreasing
the alkyl spacer length of 21 to three carbons (20) or
increasing it to five carbons (23) results in a 3-4-fold
drop in potency relative to 21. Placing a methyl group
on the phenolic oxygen of 21 gives 18 (IC50 >100 µM),
which is essentially inactive. In light of the moderate
potency of 41 (vide supra), the inactivity of 18 is
surprising and implies severe steric constraints for this
series. The effect of replacing the phenolic oxygen with
other substituents, such as a fluorine or chlorine atom,
was not investigated. Various other modifications to 21
have little effect on the NR1A/2B potency. These include
(1) incorporation of an oxygen atom into the alkyl spacer
(22); (2) addition of a hydroxy group to the 4-position of
the piperidine ring and/or to the alkyl spacer â to the
piperidine nitrogen (24, 26, and 27); (3) placement a
double bond between C3 and C4 of the piperidine ring
(25).
The 4-benzylpiperidine analogue of 21 (i.e., 30) shows
a 3-4-fold drop in potency. Decreasing the alkyl spacer
length of 30 by one carbon atom (i.e., 33) increases
potency relative to 30 but not to the same level as that
of 4-phenylpiperidine 21. The alkynyl analogues 31 and
32 show decreased potency relative to their reduced
counterparts 33 and 30. Apparently, the added rigidity
imposed by the triple bond does not allow for optimal
interaction with the receptor.
Changing the piperidine ring of 21 to a pyrrolidine
ring (i.e., 39) reduces the potency approximately 6-fold.
However, increasing the alkyl spacer length to five
carbons (40) restores the potency to that of 21.
The potency data at NR1A/2B for these three series
of molecules suggest that one factor for optimal receptor
site binding is the length of the antagonist. This length
dependence may be due to the optimization of factors
such as the fit of the ligand within the receptor pocket
or the optimization of hydrophobic interactions between
the ligand and its receptor site. Previous modeling
studies have calculated the overall length (distance
Con clu sion
Selected N-substituted 4-(4-hydroxyphenyl)piperidines,
4-(4-hydroxybenzyl)piperidines, and (()-3-(4-hydroxy-
phenyl)pyrrolidines were prepared and assayed for
NMDA receptor antagonism. All are selective for the
NR1A/2B subtype. We demonstrate that the phenolic

990 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Guzikowski et al.
a yellow solid. The solid was crystallized from MeCN/MeOH
to yield 11 as a pale beige solid (289 mg, 67%): mp 226-228
°C dec (lit.14 mp 232-235 °C); 1H NMR (300 MHz, DMSO-d6)
δ 1.45 (d, J ) 12 Hz, 2H), 1.62-1.78 (m, 2H), 2.59-2.72 (m,
2H), 2.87 (t, J ) 12 Hz, 2H), 4.52 (s, 1H), 6.66 (d, J ) 8.4 Hz,
2H), 7.22 (d, J ) 8.1 Hz, 2H), 9.18 (b, 1H).
hydroxy group, which is present in 1-4, may be
transposed to the other benzene ring while retaining
high potency, as exemplified by 21, 33, and 40. This
work provides novel insights for the design of NR2B-
selective antagonists.
4-(4-Hyd r oxyben zyl)p ip er id in e Hyd r obr om id e (15). A
solution of the HCl salt of 4-(4-methoxybenzyl)piperidine15 (14;
2.00 g, 8.27 mmol) in 48% HBr (aqueous, 30 mL) was heated
at reflux for 2 h. The solvent was removed to yield 15 as a
solid (2.25 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 1.23 (q,
J ) 14 Hz, 2H), 1.65 (d, J ) 12 Hz, 3H), 2.37 (d, J ) 6.8 Hz,
2H), 2.78 (q, J ) 11 Hz, 2H), 3.20 (d, J ) 11 Hz, 2H), 6.60 (d,
J ) 8.3 Hz, 2H), 6.90 (d, J ) 8.3 Hz, 2H), 8.18 (b, 1H), 8.50 (b,
1H), 9.15 (b, 1H).
1-Bu tyl-4-(4-m eth oxyp h en yl)p ip er id in e (17). A mixture
of the hydrochloride salt of 4-(4-methoxyphenyl)piperidine13
(16; 250 mg, 1.10 mmol), 1-bromobutane (125 µL, 159 mg, 1.16
mmol) and K2CO3 (312 mg, 2.26 mmol) in MeCN (20 mL) was
stirred at reflux for 48 h. The reaction was allowed to cool to
25 °C and added to 10% aqueous HCl (50 mL) to give a
mixture. The mixture was extracted with CHCl3 (3 × 40 mL).
The extract was washed with 10% NH4OH (80 mL) and filtered
(cotton). The solvent was removed to give a yellow solid. The
solid was purified by chromatography on silica gel with EtOH
in CHCl3 elution. Solvent removal yielded 17 as a solid (272
mg, 100%): 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J ) 7.2 Hz,
3H), 1.39 (td, J ) 15, 7.2 Hz, 2H), 1.70-1.82 (m, 2H), 1.86-
1.98 (m, 2H), 2.17-2.38 (m, 2H), 2.38-2.68 (m, 3H), 2.68-
2.82 (m, 2H), 3.33-3.46 (m, 2H), 3.79 (s, 3H), 6.84 (d, J ) 8.7
Hz, 2H), 7.18 (d, J ) 9.0 Hz, 2H).
Exp er im en ta l Section
Ch em istr y. All starting materials were commercially avail-
able and used as received unless otherwise noted. Melting
points were measured on a Thomas-Hoover or a Mel-Temp
melting point apparatus and are uncorrected. CH2Cl2 was
distilled from CaH and THF from Na/benzophenone im-
mediately prior to use. Solvent removal was routinely per-
formed on a rotoevaporator at 30-40 °C. All reactions were
performed under an inert atmosphere (Ar or N2) unless
otherwise noted. TLC analyses were performed on plastic or
glass backed F-254 silica gel plates. 1H NMR spectra were
measured on a Varian Inova or Varian Gemini spectrometer
(300 or 400 MHz). Chemical shifts are reported in δ units
1
referenced to the residual H signal of the deuterated solvent
(CHCl3, δ 7.26; CD3SOCD2H, δ 2.49; CD2HOD, δ 3.31).
Microanalyses were performed by Desert Analytics Laboratory,
Tuscon, AZ, Roberts Microlit Laboratories, Madison NJ , and
Parke-Davis Pharmaceutical Research, Ann Arbor, MI.
1-B e n zy l-4-(4-b e n zy lo x y p h e n y l)-4-h y d r o x y p ip e r i-
d in e (9). A solution of n-BuLi in hexanes (1.6 M, 68.8 mL,
110 mmol) was added to a stirred, dry ice/acetone (-78 °C)
cooled solution of 4-benzyloxybromobenzene (8; 26.5 g, 101
mmol) in THF (300 mL) to give a suspension. The suspension
was stirred at -78 °C for 30 min and a solution of 1-benzyl-
4-piperidone (19.1 g, 101 mmol) in THF (80 mL) was added
over 30 min to give a yellow solution. The solution was stirred
at -78 °C for 2 h. The cold reaction solution was added to an
ice-cold solution of NH4Cl (50 g) in H2O (350 mL). The layers
were separated and the aqueous portion was extracted with
ether (2 × 100 mL). The organic portion was washed with H2O
(2 × 100 mL) and brine (100 mL) and filtered. The filtrate
was dried (MgSO4) and the solvent was removed to give a
liquid that turned to a paste upon standing. The paste was
triturated with hexanes to give a powder. The powder was
crystallized from CH2Cl2/hexanes to yield 9 as a colorless
crystalline solid (24.4 g, 65%): mp 100-101 °C (lit.14 mp 104-
107 °C); 1H NMR (300 MHz, CDCl3) δ 1.57 (s, 1H), 1.75 (dd, J
) 12, 2.1 Hz, 2H), 2.16 (td, J ) 12, 3.6 Hz, 2H), 2.50 (t, J ) 11
Hz, 2H), 2.80 (d, J ) 12 Hz, 2H), 3.60 (s, 2H), 5.06 (s, 2H),
6.96 (d, J ) 9.0 Hz, 2H), 7.24-7.47 (m, 12H).
4-(4-Hyd r oxyp h en yl)p ip er id in e (10). Concentrated HCl
(100 mL) was added in one portion to a stirred, boiling solution
of 9 (5.00 g, 13.4 mmol) in 95% EtOH (100 mL). The resulting
solution was refluxed for 10 min and cooled to 25 °C with an
ice bath. The solution was concentrated on a rotoevaporator
at 50-55 °C to give a suspension. The solid was collected and
washed with H2O (3 × 5 mL). The collected solid was dissolved
with warming in MeOH:H2O (1:1, 100 mL) and concentrated
NH4OH (10 mL) was added to give a suspension. The suspen-
sion was extracted with CHCl3 (3 × 50 mL). The extract was
washed with H2O (3 × 50 mL) and filtered (cotton). The solvent
was removed to give a pink solid. The solid was dissolved in
warm EtOH (250 mL) and the solution was hydrogenated
(Parr) over Pd/C (10%, 1.00 g) at 50 psig for 24 h. The catalyst
was removed by filtration (Celite) and the solvent was removed
from the filtrate to give a pale yellow solid. The solid was
crystallized from MeCN/MeOH to yield 10 as a colorless solid
(1.09 g, 46%): mp 217-219 °C (lit.12 mp not reported); 1H NMR
(300 MHz, CD3OD) δ 1.61 (qd, J ) 12, 3.9 Hz, 2H), 1.78 (d, J
) 12 Hz, 2H), 2.57 (tt, J ) 12, 3.9 Hz, 1H), 2.72 (td, J ) 12,
2.7 Hz, 2H), 3.14 (d, J ) 12 Hz, 2H), 6.70 (d, J ) 8.4 Hz, 2H),
7.03 (d, J ) 8.4 Hz, 2H).
4-(4-Meth oxyp h en yl)-1-(4-p h en ylbu tyl)p ip er id in e Hy-
d r och lor id e (18). Compound 18 was prepared as described
for 17 from the hydrochloride salt of 16 (1.00 g, 4.39 mmol)
and 4-phenyl-1-tosyloxybutane27 (1.40 g, 4.61 mmol). The free
base of 18 was obtained as a beige solid (979 mg, 69%): mp
1
48-50 °C; H NMR (300 MHz, CDCl3) δ 1.52-1.86 (m, 8H),
2.01 (td, J ) 11, 3.6 Hz, 2H), 2.34-2.50 (m, 3H), 2.65 (t, J )
7.2 Hz, 2H), 2.98-3.08 (m, 2H), 3.79 (s, 3H), 6.85 (d, J ) 8.7
Hz, 2H), 7.12-7.32 (m, 7H).
Treatment of the free base of 18 with methanolic HCl
followed by crystallization from MeCN gave 18 as a colorless
crystalline solid: mp 211-213 °C; 1H NMR (300 MHz, CD3OD)
δ 1.67-2.15 (m, 8H), 2.66-2.92 (m, 3H), 3.00-3.24 (m, 4H),
3.61 (d, J ) 11 Hz, 2H), 3.76 (s, 3H), 6.87 (d, J ) 8.7 Hz, 2H),
7.13-7.33 (m, 7H). Anal. (C22H30ClNO) C, H, N.
1-Bu tyl-4-(4-h yd r oxyp h en yl)p ip er id in e Hyd r obr om id e
(19). BBr3 (1.0 M in CH2Cl2, 3.0 mL, 3.0 mmol) was added in
one portion to a stirred solution of 17 (220 mg, 890 µmol) in
CH2Cl2 (20 mL) at 0 °C. The ice bath was removed and the
solution was stirred for 1 h. The reaction was added to a
saturated aqueous NaHCO3 solution (50 mL) to give a mixture.
The mixture was stirred at 25 °C for 5 min. The layers were
separated and the aqueous portion was extracted with CH2Cl2
(4 × 30 mL). The combined organic portion was washed with
H2O (50 mL) and filtered (cotton). The solvent was removed
to give a solid. The solid was crystallized from methyl ethyl
ketone/MeOH to yield 19 as a beige solid (80 mg, 30%): mp
263-265 °C; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (t, J ) 7.5
Hz, 3H), 1.24-1.40 (m, 2H) 1.60-2.00 (m, 6H), 2.62-2.77 (m,
1H), 2.90-3.26 (m, 4H), 3.54 (d, J ) 12 Hz, 2H), 6.71 (d, J )
8.4 Hz, 2H), 7.01 (d, J ) 8.1 Hz, 2H), 9.25 (s, 1H), 9.32 (b,
1H). Anal. (C15H24BrNO) C, H, N.
4-(4-Hydr oxyph en yl)-1-(3-ph en ylpr opyl)piper idin e Hy-
d r och lor id e (20). A mixture of 10 (400 mg, 2.26 mmol),
1-bromo-3-phenylpropane (472 mg, 2.37 mmol) and NaHCO3
(199 mg, 2.37 mmol) in DMF (5 mL) was stirred at 80 °C for
18 h. The reaction was allowed to cool to 25 °C and was added
to H2O (50 mL). The mixture was extracted with CHCl3 (3 ×
50 mL). The extract was washed with H2O (2 × 50 mL) and
filtered (cotton). The solvent was removed to give a yellow
liquid. The product was purified by chromatography on silica
gel with EtOH/CHCl3 elution to give an oil. Treatment of the
oil with methanolic HCl followed by crystallization from
4-Hyd r oxy-4-(4-h yd r oxyp h en yl)p ip er id in e (11). A mix-
ture of 9 (837 mg, 2.24 mmol) and Pd/C (10% on carbon, 200
mg) in 95% EtOH (120 mL) was hydrogenated (Parr, 50 psig)
for 62 h at 25 °C. The catalyst was removed by filtration
(Celite) and the solvent was removed from the filtrate to give

Selective Antagonists at 1A/ 2B NMDA Receptor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 991
methyl ethyl ketone/MeOH yielded 20 as a colorless, crystal-
line solid (388 mg, 52%): mp 181-182 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.79-2.13 (m, 6H), 2.58-2.73 (m, 3H), 2.87-3.25
(m, 4H), 3.50 (d, J ) 12 Hz, 2H), 6.70 (d, J ) 8.7 Hz, 2H), 7.00
(d, J ) 8.7 Hz, 2H), 7.07-7.34 (m, 5H), 9.30 (s, 1H), 10.66 (b,
1H). Anal. (C20H26ClNO) C, H, N.
6.76 (d, J ) 8.7 Hz, 2H), 7.14-7.36 (m, 7H), 9.65 (s, 1H), 10.56
(b, 1H). Anal. (C21H26ClNO) C, H, N.
(()-1-(2-Hyd r oxy-4-p h en ylbu tyl)-4-(4-h yd r oxyp h en yl)-
p ip er id in e (26). A mixture of the HCl salt of 10 (350 mg,
1.64 mmol) and NaHCO3 (138 mg, 1.64 mmol) in DMF (4 mL)
was stirred at 85 °C for 10 min to give a near homogeneous
solution. Neat 4-phenylbutane 1,2-oxide16 (510 mg, 3.44 mmol)
was added and the reaction mixture was stirred overnight at
85 °C. The reaction was allowed to cool to 25 °C. The DMF
was removed in vacuo. The crude reaction product was purified
by chromatography on silica gel with EtOH in CHCl3 elution
followed by crystallization from ether/hexanes to yield 26 as
a colorless solid (225 mg, 42%): mp 154-155 °C; 1H NMR (300
MHz, CDCl3) δ 1.68-1.84 (m, 6H), 2.00 (td, J ) 16, 2.4 Hz,
1H), 2.26-2.51 (m, 4H), 2.64-2.77 (m, 1H), 2.80-2.93 (m, 2H),
3.08 (d, J ) 16 Hz, 1H), 3.67-3.78 (m, 1H), 6.77 (d, J ) 8.4
Hz, 2H), 7.07 (d, J ) 8.4 Hz, 2H), 7.14-7.32 (m, 5H). Anal.
(C21H27NO2) C, H, N.
4-(4-Hyd r oxyp h en yl)-1-(4-p h en ylbu tyl)p ip er id in e Hy-
d r obr om id e (21). Compound 21 was prepared as described
for 20 from 10 (1.70 g, 9.59 mmol) and 1-phenyl-4-tosyloxy-
butane (3.07 g, 10.1 mmol). The reaction was allowed to
proceed for 3 h. The free base was converted to the HBr salt
by treatment with 48% aqueous HBr in MeOH/ CHCl3 (1:1).
Crystallization from MeOH yielded 21 as a colorless, crystal-
line solid (1.60 g, 43%): mp 217-218 °C; 1H NMR (300 MHz,
CD3OD) δ 1.66-2.12 (m, 8H), 2.66-2.87 (m, 3H), 3.00-3.20
(m, 4H), 3.54-3.68 (m, 2H), 6.75 (d, J ) 8.4 Hz, 2H), 7.08 (d,
J ) 8.4 Hz, 2H), 7.14-7.32 (m, 5H). Anal. (C21H28BrNO) C,
H, N.
(()-4-Hydroxy-1-(2-hydroxy-4-phenylbutyl)-4-(4-hydroxy-
p h en yl)p ip er id in e (27). A mixture of 11 (300 mg, 1.55 mmol)
and 4-phenylbutane 1,2-oxide (484 mg, 3.26 mmol) in DMF (5
mL) was stirred at 80 °C for 6 h. The DMF was removed in
vacuo. The crude reaction product was purified by chroma-
tography on silica gel with EtOH in CHCl3 elution followed
by crystallization from CHCl3/hexanes to yield 27 as a colorless
solid (170 mg, 32%): 1H NMR (CDCl3) δ 1.63-1.84 (m, 4H),
2.06 (pd, J ) 13, 4.2 Hz, 2H), 2.30-2.48 (m, 3H), 2.62-2.93
(m, 5H), 3.76 (m, 1H), 6.82 (d, J ) 8.4 Hz, 2H), 7.14-7.38 (m,
7H). Anal. (C21H27NO3) C, H, N.
1-(4-(4-Hyd r oxyp h en yl)bu tyl)-4-p h en ylp ip er id in e Hy-
d r och lor id e (29). The demethylation of 1-bromo-4-(4-meth-
oxyphenyl)butane17 (28; 1.21 g, 5.00 mmol) was performed as
described for 19 to yield 1-bromo-4-(4-hydroxyphenyl)butane
as a pale yellow oil (767 mg, 67%): 1H NMR (300 MHz, DMSO-
d6) δ 1.62 (m, 2H), 1.76 (m, 2H), 2.48 (m, 2H), 3.54 (d, J ) 6.6
Hz, 2H), 6.65 (d, J ) 7.4 Hz, 2H), 6.96 (d, J ) 7.4 Hz, 2H),
9.13 (s, 1H).
A mixture of 4-phenylpiperidine (241 mg, 1.50 mmol),
1-bromo-4-(4-hydroxyphenyl)butane (366 mg, 1.60 mmol) and
NaHCO3 (315 mg, 3.75 mmol) in MeCN (50 mL) was refluxed
for 24 h. The inorganic salts were removed by passing the
reaction mixture through a short column of silica gel. The
crude reaction product was purified by chromatography on
silica gel with MeOH/EtOAc elution. The free base was treated
with methanolic HCl to yield 29 as a colorless solid (250 mg,
48%): mp 315 °C dec; 1H NMR (300 MHz, CD3OD) δ 1.69 (m,
4H), 1.94 (m, 4H), 2.80 (m, 1H), 3.06 (m, 4H), 3.26 (m, 2H),
3.56 (m, 2H), 6.65 (d, J ) 8.2 Hz, 2H), 6.97 (d, J ) 8.2 Hz,
2H), 7.25 (m, 5H). Anal. (C21H28ClNO‚1.0H2O) C, H, N.
4-(4-Hyd r oxyben zyl)-1-(4-p h en ylbu tyl)p ip er id in e Hy-
d r obr om id e (30). A mixture of 4-(4-methoxybenzyl)piperi-
dine15 (14; 600 mg, 2.92 mmol), 4-phenyl-1-tosyloxybutane (934
mg, 3.07 mmol) and K2CO3 (827 mg, 5.99 mmol) in MeCN (25
mL) was stirred at reflux for 27 h. The work up and purifica-
tion were as described for 17 to yield 4-(4-methoxybenzyl)-1-
(4-phenylbutyl)piperidine as a yellow solid (920 mg, 93%): 1H
NMR (300 MHz, CDCl3) δ 1.50-1.85 (m, 9H), 2.17-2.35 (m,
2H), 2.48-2.55 (d, J ) 6.9 Hz, 2H), 2.58-2.70 (t, J ) 7.2 Hz,
4H), 3.16-3.30 (m, 2H), 3.78 (s, 3H), 6.77-6.85 (d, J ) 8.4
Hz, 2H), 6.98-7.07 (d, J ) 8.7 Hz, 2H), 7.08-7.21 (m, 3H),
7.21-7.31 (m, 2H).
1-(2-Ben zyloxyeth yl)-4-(4-h ydr oxyph en yl)piper idin e Ci-
tr a te (22). Methanesulfonyl chloride (650 µL, 962 mg, 8.40
mmol) in CH2Cl2 (15 mL) was added to a stirred solution of
2-benzyloxyethanol (1.00 mL, 1.07 g, 7.03 mmol) in TEA (2
mL). The resulting mixture was stirred overnight at room
temperature, and washed with dilute aqueous HCl, saturated
NaHCO3 and H2O. The organic layer was dried (MgSO4) and
the crude product which was purified by chromatography on
silica gel with EtOAc/hexanes elution to yield 2-(benzyloxy)-
ethyl mesylate as a colorless liquid (679 mg, 42%): 1H NMR
(300 MHz, CDCl3) δ 3.03 (s, 3H), 3.73-3.75 (m, 2H), 4.40 (t, J
) 2.2 Hz, 2H), 4.58 (s, 2H), 7.31-7.37 (m, 5H).
Compound 22 was prepared as described for 20 from 10 (189
mg, 1.07 mmol) and 2-(benzyloxy)ethyl mesylate (234 mg, 1.02
mmol). The reaction was allowed to proceed for 18 h. The free
base was treated with citric acid in MeOH. Solvent removal
and trituration with ether yielded 22 as a colorless, hygroscopic
solid (133 mg, 26%): 1H NMR (300 MHz, CD3OD) δ 1.98 (s,
4H), 2.70-2.85 (m, 6H), 3.09 (b, 1H), 3.37 (s, 2H), 3.62 (d, J )
11 Hz, 2H), 3.82 (s, 2H), 4.58 (s, 2H), 6.73 (d, J ) 7.6 Hz, 2H),
7.07 (d, J ) 7.6 Hz, 2H), 7.37 (s, 5H). Anal. (C26H33NO9‚
0.25H2O) C, H, N.
4-(4-Hydr oxyph en yl)-1-(5-ph en ylpen tyl)piper idin e Hy-
d r och lor id e (23). Compound 23 was prepared as described
for 20 from the hydrochloride salt of 10 (350 mg, 1.64 mmol)
and 1-phenyl-5-tosyloxypentane28 (548 mg, 1.72 mmol). The
reaction was allowed to proceed for 20 h. Treatment of the free
base with methanolic HCl followed by crystallization from
MeCN yielded 23 as a colorless, crystalline solid (327 mg,
55%): mp 169-171 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.24-
1.37 (m, 2H), 1.52-2.08 (m, 8H), 2.54-2.73 (m, 3H), 2.84-
3.04 (m, 4H), 3.48 (d, J ) 16 Hz, 2H), 6.70 (d, J ) 8.4 Hz, 2H),
7.00 (d, J ) 8.7 Hz, 2H), 7.12-7.31 (m, 5H), 9.29 (s, 1H), 10.45
(b, 1H). Anal. (C22H30ClNO) C, H, N.
4-Hyd r oxy-4-(4-h yd r oxyp h en yl)-1-(4-p h en ylbu tyl)p ip -
er id in e (24). Compound 24 was prepared as described for 20
from 11 (280 mg, 1.45 mmol) and 1-phenyl-4-tosyloxybutane
(463 mg, 1.52 mmol). The reaction was allowed to proceed for
3 h. After chromatography, the free base was crystallized from
MeCN to yield 24 as a colorless, crystalline solid (287 mg,
61%): mp 157-159 °C dec; 1H NMR (300 MHz, CDCl3) δ 1.38-
1.65 (m, 6H), 1.77-1.94 (m, 2H), 2.23-2.75 (m, 8H), 4.58 (b,
1H), 6.67 (d, J ) 8.4 Hz, 2H), 7.10-7.32 (m, 7H), 9.19 (s, 1H).
Anal. (C21H27NO2‚0.2H2O) C, H, N.
1,2,5,6-Tet r a h yd r o-4-(4-h yd r oxyp h en yl)-1-(4-p h en yl-
bu tyl)p yr id in e Hyd r och lor id e (25). Aqueous, concentrated
HCl (4 mL) was added dropwise over 30 s to a stirred boiling
solution of 24 (150 mg, 461 µmol) in absolute EtOH (4 mL).
The resulting solution was stirred at reflux for 6 min to give
a suspension. The suspension was allowed to cool to 25 °C.
The suspended solid was collected, washed with H2O (3 × 1
mL) and dried to yield 25 as a pale yellow crystalline solid
(145 mg, 91%): mp 230-231 °C dec; 1H NMR (300 MHz,
DMSO-d6) δ 1.53-1.85 (m, 4H), 2.54-2.88 (m, 4H), 3.04-3.24
(m, 3H), 3.49-3.75 (m, 2H), 3.82-3.99 (m, 1H), 5.98 (s, 1H),
Demethylation of the intermediate methoxy compound (905
mg, 2.68 mmol) was performed as described for 19. Crystal-
lization of the reaction product from methyl ethyl ketone/
MeOH yielded 30 as a light brown solid (97 mg, 9%): mp 163-
1
164 °C; H NMR (300 MHz, DMSO-d6) δ 1.26-1.82 (m, 9H),
2.34-2.46 (m, 2H), 2.58 (t, J ) 6.9 Hz, 2H), 2.72-3.20 (m, 4H),
3.40 (d, J ) 13 Hz, 2H), 6.66 (d, J ) 7.8 Hz, 2H), 6.94 (d, J )
8.1 Hz, 2H), 7.12-7.35 (m, 5H), 9.02 (b, 1H), 9.18 (s, 1H). Anal.
(C22H30BrNO) C, H, N.
4-(4-H yd r oxyb e n zyl)-1-(4-p h e n yl-3-b u t yn yl)p ip e r i-
d in e (32). A mixture of 4-(4-hydroxybenzyl)piperidine (15; 2.25
g, 8.27 mmol), 1-tosyloxy-3-butyne18 (1.85 g, 8.27 mmol) and
NaHCO3 (2.10 g, 25.0 mmol) in DMF (50 mL) was stirred at

992 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Guzikowski et al.
80 °C for 18 h. The DMF was removed and the residue was
partitioned between ether and water. The ether portion was
washed with brine and dried (MgSO4). The ether was removed
and the residue was purified by chromatography on silica gel
with EtOAc elution to yield 1-(3-butynyl)-4-(4-hydroxybenzyl)-
piperidine as a solid (800 mg, 40%): mp 137-138 °C; 1H NMR
(400 MHz, CDCl3) δ 1.30 (qq, J ) 14.2, 7.1 Hz, 2H), 1.40 (m,
1H), 1.60 (d, J ) 12.2 Hz, 2H), 1.90 (m, 2H), 1.95 (s, 1H), 2.35
(m, 1H), 2.42 (d, J ) 6.8 Hz, 1H), 2.57 (t, J ) 7.3 Hz, 2H),
2.90 (d, J ) 12.5 Hz, 2H), 6.82 (d, J ) 8.3 Hz, 2H), 6.97 (d, J
) 8.3 Hz, 2H).
A mixture of 1-(3-butynyl)-4-(4-hydroxybenzyl)piperidine
(730 mg, 3.00 mmol), iodobenzene (630 mg, 3.09 mmol) and
Pd(Ph3P)4 (176 mg, 152 µmol) in pyrrolidine (20 mL) was
stirred for 3 days at 25 °C. The pyrrolidine was removed and
the residue was purified by chromatography on silica gel with
EtOAc elution. Crystallization from EtOAc yielded 32 as a
solid (600 mg, 62%): mp 136-138 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.05-1.23 (m, 2H), 1.27-1.45 (m, 1H), 1.52 (d, J
) 12 Hz, 2H), 1.82-2.04 (m, 2H), 2.36 (d, J ) 6.6 Hz, 2H),
2.50-2.62 (m, 4H), 2.87 (d, J ) 8.4 Hz 2H), 6.63 (d, J ) 8.1
Hz, 2H), 6.90 (d, J ) 8.1 Hz, 2H), 7.28-7.44 (m, 5H), 9.09 (s,
1H). Anal. (C22H25NO‚0.50H2O) C, H, N.
1.22 (m, 6H), 2.61 (dd, J ) 16, 5.4 Hz, 1H), 3.14 (dd, J ) 17,
10 Hz, 1H), 3.71 (s, 1H), 3.80 (s, 3H), 4.10-4.30 (m, 4H), 6.87
(d, J ) 8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz, 2H).
A mixture of the above diethyl ester (2.50 g 8.93 mmol) and
LiAlH4 (1.40 g, 37.0 mmol) in THF (50 mL) was stirred at
reflux for 3 h. Water (10 mL) was added. The solid was
removed by filtration and washed with CH2Cl2 (2 × 10 mL).
The organic solution was diluted with ether (100 mL) and
washed with brine (2 × 100 mL). The organic portion was dried
(Na2SO4) and the solvent was removed. The crude product was
purified by chromatography on silica gel with EtOAc/hexanes
elution to give 2-(4-methoxyphenyl)butane-1,4-diol as an oil
(1.20 g, 69%): 1H NMR (300 MHz, CDCl3) δ 1.85 (m, 1H), 1.98
(m, 1H), 2.92 (p, J ) 6.9 Hz, 1H), 3.5-3.7 (m, 4H), 3.80 (s,
3H), 6.86 (d, J ) 8.4 Hz, 2H), 7.13 (d, J ) 8.4 Hz, 2H).
A solution of the above diol (1.00 g, 5.10 mmol), TEA (2.13
mL, 1.55 g, 15.3 mmol), methanesulfonyl chloride (1.20 mL,
1.78 g, 15.5 mmol) and DMAP (150 mg, 1.22 mmol) in CH2Cl2
(15 mL) was stirred at room temperature for 6 h. The reaction
solution was diluted with CH2Cl2 (20 mL) and washed with
NH4Cl solution (20 mL) and brine (20 mL). The organic portion
was dried (Na2SO4) and the solvent was removed. The crude
product was purified by chromatography on silica gel with
EtOAc/hexanes elution to yield 36 as a colorless oil (1.70 g,
94%): 1H NMR (300 MHz, CDCl3) δ 2.07 (m, 1H), 2.33 (m,
1H), 2.88 (s, 3H), 2.93 (s, 3H), 3.19 (m, 1H), 3.80 (s, 3H), 4.00-
4.40 (m, 4H), 6.78 (d, J ) 8.7 Hz, 2H), 7.16 (d, J ) 8.4 Hz,
2H).
(()-3-(4-Me t h oxyp h e n yl)-1-(4-p h e n ylb u t yl)p yr r oli-
d in e (37). A mixture of 36 (750 mg, 2.12 mmol) and 4-phenyl-
butylamine (3.30 mL, 3.11 g, 465 mmol) was stirred at 100 °C
for 12 h. The excess amine was removed in vacuo. The crude
product was purified by chromatography on silica gel with
MeOH/CH2Cl2 elution to give 37 as a colorless oil (420 mg,
64%): 1H NMR (300 MHz, CDCl3) δ 1.50-1.90 (m, 6H), 2.20-
2.60 (m, 6H), 2.83 (m, 1H), 3.03 (t, J ) 8.1, 1H), 3.30 (m, 1H),
3.79 (s, 3H), 6.86 (d, J ) 8.4 Hz, 2H), 7.00-7.30 (m, 7H).
(()-3-(4-Met h oxyp h en yl)-1-(5-p h en ylp en t yl)p yr r oli-
d in e (38). Compound 38 was prepared as described for 37
from 36 (420 mg, 1.19 mmol) and 5-phenylpentylamine20 (430
mg, 2.67 mmol) to yield 38 as a colorless oil (110 mg, 29%):
1H NMR (300 MHz, CDCl3) δ 1.40 (p, J ) 8.1 Hz, 2H), 1.64
(m, 4H), 1.89 (m, 1H), 2.31 (m, 1H), 2.40-2.80 (m, 6H), 2.96
(m, 1H), 3.14 (m, 1H), 3.36 (p, J ) 8.7 Hz, 1H), 3.80 (s, 3H),
6.86 (d, J ) 8.4 Hz, 2H), 7.00-7.30 (m, 7H).
4-(4-H yd r oxyb en zyl)-1-(3-p h en yl-2-p r op yn yl)p ip er i-
d in e (31). Compound 31 was prepared as described for 32
using 3-tosyloxy-1-propyne to yield 31 as a solid: mp 154-
1
155 °C; H NMR (300 MHz, DMSO-d6) δ 1.07-1.24 (m, 2H),
1.28-1.44 (m, 1H), 1.54 (d, J ) 12 Hz, 2H), 2.09 (t, J ) 11 Hz,
2H), 2.35 (d, J ) 6.9 Hz, 2H), 2.80 (d, J ) 11 Hz, 2H), 3.44 (s,
2H), 6.63 (d, J ) 8.1 Hz, 2H), 6.91 (d, J ) 8.1 Hz, 2H), 7.27-
7.45 (m, 5H), 9.10 (s, 1H). Anal. (C21H23NO) C, H, N.
4-(4-Hydr oxyben zyl)-1-(3-ph en ylpr opyl)piper idin e (33).
A mixture of 31 (420 mg, 1.38 mmol) and Pd/C (20%, 100 mg)
in MeOH/THF (1:1, 75 mL) was hydrogenated (Parr, 50 psig)
until H2 uptake ceased. The catalyst was removed by filtration
and the solvent was removed from the filtrate. The residue
was triturated with ether to yield 33 as a solid (350 mg, 82%):
1
mp 133-135 °C; H NMR (300 MHz, DMSO-d6) δ 1.03-1.20
(m, 2H), 1.24-1.42 (m, 1H), 1.49 (d, J ) 12 Hz, 2H), 1.60-
1.82 (m, 4H), 2.19 (t, J ) 6.9 Hz, 2H), 2.34 (d, J ) 6.6 Hz,
2H), 2.53 (t, J ) 7.5 Hz, 2H), 2.76 (d, J ) 11 Hz, 2H), 6.63 (d,
J ) 7.2 Hz, 2H), 6.90 (d, J ) 6.9 Hz, 2H), 7.20-7.65 (m, 5H),
9.11 (b, 1H). Anal. (C21H27NO‚0.30H2O) C, H, N.
2-(4-Met h oxyp h en yl)m a leic a cid Diet h yl E st er (35).
The general procedure of Dean and Blum19 was employed. A
mixture of 4-methoxybenzyl cyanide (34; 10.0 g, 68.0 mmol),
glyoxylic acid monohydrate (12.5 g, 136 mmol), and K2CO3
(37.0 g, 268 mmol) in MeOH (100 mL) was stirred at reflux
for 24 h to give a thick suspension. The solid was collected by
filtration and washed with CH2Cl2. The collected solid was
suspended in H2O (500 mL) and the suspension was stirred
overnight. The solid was collected and air-dried to yield (Z)-
3-(4-methoxyphenyl)-3-cyano-2-propenoic acid potassium salt
as a colorless solid (8.00 g, 52%): 1H NMR (300 MHz, DMSO-
d6) δ 3.80 (s, 3H), 6.92 (s, 1H), 6.98 (d, J ) 8.7 Hz, 2H), 7.49
(d, J ) 7.5 Hz, 2H).
A solution of the above solid (5.00 g, 22.2 mmol) and
concentrated H2SO4 (20 mL) in EtOH (50 mL) was stirred at
reflux for 5 h. The solvent was removed to give an oil. The oil
was mixed with aqueous NaHCO3 (100 mL) and the mixture
was extracted with CH2Cl2 (3 × 50 mL). The organic portion
was washed with brine (100 mL) and dried (Na2SO4). The
solvent was removed to give an oil. The crude product was
purified by chromatography on silica gel with CH2Cl2 elution
to yield 35 as an oil (4.40 g, 71%): 1H NMR (300 MHz, CDCl3)
δ 1.31 (t, J ) 6.9 Hz, 3H), 1.36 (t, J ) 7.2 Hz, 3H), 3.84 (s,
3H), 4.23 (q, J ) 7.2 Hz, 2H), 4.42 (q, J ) 7.2 Hz, 2H), 6.22 (s,
1H), 6.93 (d, J ) 9.0 Hz, 2H), 7.42 (d, J ) 9.0 Hz, 2H).
(()-3-(4-H yd r oxyp h e n yl)-1-(4-p h e n ylb u t yl)p yr r oli-
d in e (39). Boron tribromide (1 M in CH2Cl2, 400 µL) was
added to a stirred solution of 37 (400 mg, 1.29 mmol) in CH2Cl2
(2 mL) and the resulting mixture was stirred at room tem-
perature for 3 h. Water (3 mL) was added followed by NH4OH
(10 mL). The mixture was stirred for 10 min and diluted with
H2O (30 mL). The mixture was extracted with CH2Cl2 (3 × 30
mL) and the extract was washed with brine (50 mL). The
extract was dried (Na2SO4) and the solvent was removed. The
crude product was purified by chromatography on silica gel
with MeOH/CH2Cl2 elution followed by crystallization from
MeOH/ CH2Cl2 to give 39 as a colorless solid (120 mg, 31%):
1
mp 109-110 °C; H NMR (300 MHz, CDCl3) δ 1.60 (m, 4H),
1.84 (m, 1H), 2.28 (m, 1H), 2.40-2.60 (m, 6H), 2.87 (m, 1H),
3.07 (t, J ) 8.1 Hz, 1H), 3.31 (p, J ) 8.4 Hz, 1H), 6.72 (d, J )
8.7 Hz, 2H), 7.00-7.40 (m, 7H). Anal. (C20H25NO) C, H, N.
(()-3-(4-H yd r oxyp h en yl)-1-(5-p h en ylp en t yl)p yr r oli-
d in e (40). Compound 40 was prepared as described for 39
from 38 (100 mg, 309 µmol) to yield 40 as a colorless solid (13
mg, 14%): mp 107-108 °C; 1H NMR (300 MHz, CDCl3) δ 1.38
(m, 2H), 1.65 (m, 4H), 1.88 (m, 1H), 2.29 (m, 1H), 2.40-2.80
(m, 6H), 2.94 (m, 1H), 3.13 (m, 1H), 3.45 (m, 1H), 6.74 (d, J )
8.4 Hz, 2H), 7.00-7.40 (m, 7H). Anal. (C21H27NO) C, H, N.
Electr op h ysiology Da ta An a lysis. The methods em-
ployed were described previously.9a
2-(4-Meth oxyph en yl)bu ta n e 1,4-Dim esyla te (36). A mix-
ture of 35 (2.90 g, 10.4 mmol) and Pd/C (10% on carbon, 100
mg) in EtOH (30 mL) was stirred under H2 (ambient pressure)
for 24 h. The catalyst was removed by filtration and the solvent
was removed to give 2-(4-methoxyphenyl)succinic acid diethyl
ester as an oil (2.92 g, 100%): 1H NMR (300 MHz, CDCl3) δ
Molecu la r Mod elin g. The methods employed were de-
scribed previously.9b
[3H]P r a zosin Bin d in g Assa y. This assay was modified
from previously described methods.21 Frozen Sprague-Dawley

Selective Antagonists at 1A/ 2B NMDA Receptor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 993
(4) (a) Moriyoshi, K. M.; Masu, M.; Ishii, T.; Shigemoto, R.; Mizuno,
N.; Nakanishi, S. Molecular Cloning and Characterization of the
Rat NMDA Receptor. Nature (London) 1991, 354, 31-37. (b)
Sugihara, H.; Moriyoshi, K.; Ishii, T.; Masayuki, M.; Nakanishi,
S. Structures and Properties of Seven Isoforms of the NMDA
Receptor Generated by Alternative Splicing. Biochem. Biophys.
Res. Commun. 1992, 185, 826-832. (c) Monyer, H.; Sprengel,
R.; Schoeper, R.; Herb, A.; Higuchi, M.; Lomeli, H.; Burnashev,
N.; Sakmann, B.; Seeburg, P. H. Heteromeric NMDA Recep-
tors: Molecular and Functional Distinction of Subtypes. Science
1992, 256, 1217-1221. (d) Monyer, H.; Burnashev, N.; Laurie,
D. J .; Sakmann, B.; Seeburg, P. H. Developmental and Regional
Expression in the Rat Brain and Functional Properties of Four
NMDA Receptors. Neuron 1994, 12, 529-540.
(5) (a) Williams, K. Ifenprodil Discriminates Subtypes of the N-
Methyl-D-aspartate Receptor: Selectivity and Mechanism at
Recombinant Heteromeric Receptors. Mol. Pharmacol. 1993, 44,
851-859. (b) Chenard, B. L.; Shalaby, I. A.; Koe, B. K.; Ronau,
R. T.; Butler, T. W.; Prochniak M. A.; Schmidt, A. W.; Fox C. B.
Separation of R1 Adrenergic and N-Methyl-D-aspartate Antago-
nist Activity in a Series of Ifenprodil Compounds. J . Med. Chem.
1991, 34, 3085-3090.
(6) Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J . N. C.;
Mohacsi, E.; Heitz, M. P.; Kemp, J . A. Ro25-6981, a Highly
Potent and Selective Blocker of N-Methyl-D-aspartate Receptors
Containing the NR2B subunit. Characterization in vitro. J .
Pharmacol. Exp. Ther. 1997, 283, 1285-1292.
(7) Chenard, B. L.; Bordner, J .; Butler, T. W.; Chembers, L. K.;
Collins, M. A.; De Costa, D. L.; Ducat, M. F.; Dumont, M. L.;
Fox, C. B.; Mena, E. E.; Menniti, F. S.; Nielsen, J .; Pagnozzi, M.
J .; Richter, K. E. G.; Ronau, R. T.; Shalaby, I. A.; Stemple, J . Z.;
White, W. F. (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phen-
ylpiperidino)-1-propanol: A Potent New Neuroprotectant which
Blocks N-Methyl-D-aspartate Responses. J . Med. Chem. 1995,
38, 3138-3145.
rat cortices obtained from ABS (Wilmington, DE) were thawed,
homogenized in 10 volumes of ice-cold 0.25 M sucrose/10 mM
Tris-HCl, pH 7.4 buffer, and centrifuged at 1000g for 10 min
at 4 °C. The supernatant was centrifuged at 40000g for 30
min; the pellet was resuspended in 10 volumes of ice-cold 140
mM NaCl/5 mM MgCl2/50 mM Tris-HCl, pH 7.4 buffer
(prazosin binding buffer), and centrifuged at 40000g for 30
min. The pellet was resuspended in prazosin binding buffer
and centrifuged twice more for a total of three wash steps,
and the final pellet was stored at -80 °C. On the day of the
binding assay, the membrane pellets were thawed and resus-
pended in prazosin binding buffer, and 200 µg of membrane
protein was incubated with 0.8 nM [3H]prazosin (∼80 Ci/mmol;
NEN, Boston, MA). Nonspecific binding was determined in the
presence of 10 µM phentolamine.
[3H]Ra clop r id e Bin d in g Assa y. This assay was modified
from previously described methods.22 Frozen Sprague-Dawley
rat striata obtained from ABS (Wilmington, DE) were thawed,
homogenized in ice-cold 50 mM Tris-HCl, pH 7.4 buffer (8-9
pairs of striata/10 mL), and centrifuged at 20000g for 10 min
at 4 °C. The pellet was resuspended in 10 mL of ice-cold 50
mM Tris-HCl, pH 7.4 buffer, and centrifuged at 20000g for 10
min. The pellet was resuspended in 120 mM NaCl/5 mM KCl/
50 mM Tris-HCl, pH 7.4 buffer (raclopride binding buffer) (1
mL/pair of striata) and was stored at -80 °C. On the day of
the binding assay, the membrane suspensions were thawed
and diluted in raclopride binding buffer, and 200 µg of
membrane protein was incubated with 3 nM [3H]raclopride
(∼80 Ci/mmol; NEN). Nonspecific binding was determined in
the presence of 300 µM sulpiride.
Mou se MES Stu d ies. General methods for MES studies
were performed as previously reported.23 Briefly, seizures were
induced in male Swiss Webster mice (body weight 23-27 g,
housed with ad libitum food and water) via corneal electrodes
(ECT 7801, Ugo Basile). Rectagular pulses (50 mA, 60-75 Hz,
0.8 ms width, 0.2 s train length) were employed. Seizure
occurrence was recorded as a tonic hind-limb extension after
electroshock stimulus. Test compounds were formulated for
iv administration as 5 mg/mL solutions in 0.2 M tris(hy-
droxymethyl)aminomethane. The vehicle alone induced no
detectable levels of protection. ED50 and 95% confidence limits
were calculated by Litchfield and Wilcoxon analysis (Micro-
Computer Specialists, Philadelphia, PA).
(8) Zhou, Z. L.; Cai, S. X.; Whittemore, E. R.; Konkoy, C. S.; Espitia,
S. A.; Tran, M.; Rock, D. M.; Coughenour, L. L.; Hawkinson, J .
E.; Boxer, P. A.; Bigge, C. F.; Wise, L. D.; Weber, E.; Woodward,
R. M.; Keana, J . F. W. 4-Hydroxy-1-[2-(4-hydoxyphenyl)ethyl)-
(4-methylbenzyl)piperidine: A Novel, Potent and Selective 1A/
2B NMDA Receptor Antagaonist. J . Med. Chem. 1999, 42, 2993-
3000.
(9) (a) Whittemore, E. R.; Ilyin, V. I.; Konkoy, C. S.; Woodward, R.
M. Subtype-selective Antagonism of NMDA Receptors by Nylid-
rin. Eur. J . Pharmacol. 1997, 337, 197-208. (b) Tamiz, A. P.;
Whittemore, E. R.; Zhou, Z. L.; Huang, J . C.; Drewe, J . A.; Chen,
J . C.; Cai, S. X.; Weber, E.; Woodward, R. M.; Keana, J . F. W.
Structure-Activity Relationships for a Series of Bis(phenyl-
alkyl)amines: Potent Subtype-Selective Inhibitors of N-Methyl-
D-aspartate Receptors. J . Med. Chem. 1998, 41, 3499-3506.
(10) (a) Tamiz, A. P.; Whittemore, E. R.; Schelkun, R. M.; Yuen, P.
W.; Woodward, R. M.; Cai, S. X.; Weber, E.; Keana, J . F. W. N-(2-
(4-Hydroxyphenyl)ethyl)-4-chlorocinnamide: A Novel Antagonist
at the 1A/2B NMDA Receptor Site. Bioorg. Med. Chem. Lett.
1998, 8, 199-200. (b) Tamiz, A. P.; Cai, S. X.; Zhou, Z. L.; Yuen,
P. W.; Schelkun, R. M.; Whittemore, E. R.; Weber, E.; Woodward,
R. M.; Keana, J . F. W. Structure Activity Relationship of
N-(Phenylalkyl)cinnamides as Novel NR2B Subtype Selective
NMDA Receptor Antagonists. J . Med. Chem. 1999, 17, 3412-
3420.
Ack n ow led gm en t. Financial support was provided
by CoCensys, Inc. and Parke-Davis Pharmaceutical
Research. We thank Dr. L. Zhang (CoCensys) for the
preparation of NMDA receptor (NR1A/2A, NR1A/2B, and
NR1A/2C) cRNA and Dr. Peter H. Seeburg (University
of Heidelberg, Heidelberg, Germany) for the NMDA
receptor clones.
(11) Replacing the p-hydroxy group of 6 and 7 with a chloro group
results in a substantial loss of potency at the NR1A/2B subtype
(see ref 10).
(12) J acobs, R. T.; Shenvi, A. B. 4-(Aryl-substituted)-piperidines as
Neurokinin Receptor Antagonists. Eur. Patent Appl. 630887A1,
Dec 28, 1994.
(13) Allen & Hansbury Ltd. Neth. Appl. 6,510,107, Feb 7, 1966;
Chem. Abstr. 1966, 65, 7155a.
(14) Emonds-Alt, X.; Goulaouic, P.; Proietto, V.; van Broeck, D.
Arylalkylamines, Process for Their Preparation and Pharma-
ceutical Compositions Containing Them. Eur. Patent Appl.
474561A1, Mar 11, 1992.
Refer en ces
(1) (a) McCulloch, J . Excitatory Amino Acid Antagonists and their
Potential for the Treatment of Ischeamic Brain Damage in Man.
Br. J . Clin. Pharmacol. 1992, 34, 106-114. (b) Rogawski, M. A.
The NMDA Receptor, NMDA Antagonists and Epilepsy Therapy.
A Status Report. Drugs 1992, 44, 279-292. (c) Starr, M. S.
Antiparkinsonian Actions of Glutamate Antagonists - Alone and
with L-Dopa: A Review of Evidence and Suggestions for Possible
Mechanisms. J . Neural. Transm. Parkinson’s Dis. Dementia Sect.
1995, 10, 141-185.
(2) (a) Olney, J . W.; Labruyere, J .; Price, M. T. Pathological Changes
Induced in Cerebrocortical Neurons by Phencyclidine and Re-
lated Drugs. Science (Washington, DC) 1989, 244, 1360-1362.
(b) Willetts, J .; Balster, R. L. The Discriminative Stimulus
Effects of N-Methyl-D-aspartate Antagonists in Phencyclidine-
trained Rats. Neuropharmacology 1988, 27, 1249-1256. (c)
Tricklebank, M. D.; Singh, L.; Oles, R. J .; Preston, C.; Iversen,
S. D. The Behavioral Effects of MK-801: A Comparison with
Antagonists Acting Noncompetitively and Competitively at the
NMDA Receptor. Eur. J . Pharmacol. 1989, 167, 127-135.
(3) For a review see: Chenard, B. L.; Menniti, F. S. Antagonists
Selective for NMDA Receptors Containing the NR2B Subunit.
Curr. Pharm. Des. 1999, 5, 381-404.
(15) Gray, A. P.; Heitmeir, D. E.; Godberg, M. E. Treatment of
Depression with 4-Substituted Piperidines. U.S. Patent 3632767,
J an 4, 1972.
(16) Schwan, A. L.; Roche, M. R.; Gallagher, J . F.; Ferguson, G. On
the Conformational Preferences of the Dehydrochlorination of
R-chlorosulfoxides. Can. J . Chem. 1994, 72, 312-324.
(17) Henely-Smith, P.; Whiting, D. A.; Wood, A. F. Methods for the
Construction of Linear 1,7-Diarylheptanoids; Synthesis of Di-
O-methylcentrolobol and Precursors (Synthetic and Biosynthetic)
to the meta,meta-Bridged Biphenyls Myricanol and Myricanone.
J . Chem. Soc., Perkin Trans. 1 1980, 614-622.

994 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Guzikowski et al.
(18) Glase, S. A.; Akunne, H. C.; Heffner, T. G.; J aen, J . C.;
MacKenzie, R. G.; Meltzer, L. T.; Pugsley, T. A.; Smith, S. J .;
Wise, L. D. Aryl 1-But-3-ynyl-4-phenyl-1,2,3,6-tetrahydro-
pyridines as Potential Antipsychotic Agents: Synthesis and
Structure Activity Relationships. J . Med. Chem. 1996, 39, 3179-
3187.
(19) Dean, W. D.; Blum, D. M. Condensation of Arylacetonitriles with
Glyoxylic Acid. Facile Synthesis of Arylmaleic Acid Derivatives.
J . Org. Chem. 1993, 58, 7916-7917.
(20) Lever, O. W.; Bell, L. N.; McGuire, H. M.; Ferone, R. Monocyclic
Pteridine Analogues. Inhibition of Escherichia Coli Dihydro-
pteroate Synthase by 6-Amino-5-nitrosoiso-cytosines. J . Med.
Chem. 1985, 28, 1870-1874.
(21) (a) Tsuchihashi, H.; Maruyama, K.; Baba, S.; Mano, F.; Kinami,
J .; Nagatomo, T. Comparison of R1 Adrenoreceptors Between Rat
Brain and Spleen. J pn. J . Pharmacol. 1991, 56, 523-530. (b)
Veenstra, D. M.; van Buuren, K. J .; Krielaart, M. J .; Nijkamp,
F. P. Errors Introduced in Radioligand Binding Studies Due to
Displaceable, Cation Dependent, [3H]Prazosin Binding to Glass-
Fibre Filters and Glass Surfaces. J . Receptor Res. 1993, 13, 801-
814.
(24) (a) Hashimoto, K.; London, E. D. Further Characterization of
[3H]infenprodil Binding to Sigma Receptors in Rat Brain. Eur.
J . Pharmacol. 1993, 236, 159-163. (b) Takahashi, H.; Kirsch,
J . R.; Hashimoto, K.; London, E. D.; Koehler, R. C.; Traystman,
R. PPBP (4-Phenyl-1-(4-phenylbutyl) piperidine), a Potent Sigma
Receptor Ligand, Decreases Brain Injury After Transient Focal
Ischemia in Cats. Stroke 1995, 26, 1676-1682.
(25) (a) Whittemore, E. R.; Ilyin, V. I.; Woodward, R. M. Antagonism
of N-Methyl-D-aspartate Receptors by Sigma Site Ligands:
Potency, Subtype-selectivity, and Mechanisms of Inhibition. J .
Pharmacol. Exp. Ther. 1997, 282, 326-338. (b) Ilyin, V. I.;
Whittemore, E. R.; Guastella, J .; Weber, E.; Woodward, R. M.
Subtype Selective Inhibition of N-Methyl-D-aspartate Receptors
by Haloperidol. Mol. Pharmacol. 1996, 50, 1541-1550.
(26) Novascreen is a division of Oceanix Biosciences Corp., 7170
Standard Dr., Hanover, MD 21076-1334.
(27) Subbarao, K. V.; Damodaran, N. P.; Dev, S. Photochemical
Transformations V Organic Iodides (Part 4): Solution Photo-
chemistry of 4-Phenyl-1-iodobutane and 4-Phenyl-1-bromo-
butane. Tetrahedron 1987, 43, 2543-2548.
(28) Pang, Y. P.; Hong, F.; Quiram, P.; J elacic, T.; Brimijoin, S.
Synthesis of Alkylene Linked Bis-THA as Highly Potent and
Selective Inhibitors and Molecular Probes of Acetylcholinest-
erase. J . Chem. Soc., Perkin Trans. 1 1997, 171-176.
(22) Dewar, K. M.; Montreuil, B.; Grondin, L.; Reader, T. A. Dopam-
ine D2 Receptors Labeled with [3H]Raclopride in Rat and Rabbit
Brains. Equilibrium Binding, Kinetics, Distribution and Selec-
tivity. J . Pharmacol. Exp. Ther. 1989, 250, 696-706.
(23) Swinyard, E. A. Assay of Antiepileptic Drug Activity in Experi-
mental Animals: Standard Tests. In Anticonvulsant Drugs.
International Encyclopedia of Pharmacology and Therapeutics;
Mercier, J ., Ed.; Pergamon Press: Oxford, 1972; pp 47-65.
J M990428C